Macrophage-derived netrin-1 drives adrenergic nerve–associated lung fibrosis
Ruijuan Gao, … , Holger K. Eltzschig, Erica L. Herzog
Ruijuan Gao, … , Holger K. Eltzschig, Erica L. Herzog
Published January 4, 2021
Citation Information: J Clin Invest. 2021;131(1):e136542. https://doi.org/10.1172/JCI136542.
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Research Article Pulmonology

Macrophage-derived netrin-1 drives adrenergic nerve–associated lung fibrosis

Abstract

Fibrosis is a macrophage-driven process of uncontrolled extracellular matrix accumulation. Neuronal guidance proteins such as netrin-1 promote inflammatory scarring. We found that macrophage-derived netrin-1 stimulates fibrosis through its neuronal guidance functions. In mice, fibrosis due to inhaled bleomycin engendered netrin-1–expressing macrophages and fibroblasts, remodeled adrenergic nerves, and augmented noradrenaline. Cell-specific knockout mice showed that collagen accumulation, fibrotic histology, and nerve-associated endpoints required netrin-1 of macrophage but not fibroblast origin. Adrenergic denervation; haploinsufficiency of netrin-1’s receptor, deleted in colorectal carcinoma; and therapeutic α1 adrenoreceptor antagonism improved collagen content and histology. An idiopathic pulmonary fibrosis (IPF) lung microarray data set showed increased netrin-1 expression. IPF lung tissues were enriched for netrin-1+ macrophages and noradrenaline. A longitudinal IPF cohort showed improved survival in patients prescribed α1 adrenoreceptor blockade. This work showed that macrophages stimulate lung fibrosis via netrin-1–driven adrenergic processes and introduced α1 blockers as a potentially new fibrotic therapy.

Authors

Ruijuan Gao, Xueyan Peng, Carrighan Perry, Huanxing Sun, Aglaia Ntokou, Changwan Ryu, Jose L. Gomez, Benjamin C. Reeves, Anjali Walia, Naftali Kaminski, Nir Neumark, Genta Ishikawa, Katharine E. Black, Lida P. Hariri, Meagan W. Moore, Mridu Gulati, Robert J. Homer, Daniel M. Greif, Holger K. Eltzschig, Erica L. Herzog

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Figure 5

NTN1 expression, noradrenaline content, and effect of α1 adrenoreceptor antagonist use on survival in human IPF.

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NTN1 expression, noradrenaline content, and effect of α1 adrenoreceptor ...
(A) Evaluation of publicly available microarray data from the LGRC cohort revealed that relative to the controls (n = 50, round symbol), IPF lungs (n = 119, triangle) exhibited higher NTN1 expression (6.3 ± 0.3 vs. 6.1 ± 0.2, [log2], FDR-adjusted P < 0.01). (B) Compared with the control, the expression of NTN1 relative to ACTB was increased in IPF lung tissues (P = 0.0398, Mann-Whitney comparison). (C–F) Immunofluorescence detection of NTN1 (red) and Mac1 (green) in archived lung biopsy specimens from controls (C and D) and IPF patients (E and F). The boxed areas in the low-power views are shown directly beneath. Slides were counterstained with DAPI (blue). Original magnification, ×20. (G) Compared with control samples, the number of Mac1+ cells coexpressing NTN1 counted per high-powered field (HPF) was increased in IPF (P = 0.0073, 2-tailed Student’s t test). (H) Compared with explanted donor lung tissues, the NA/A ratio was increased in IPF lungs obtained at the time of transplant (P = 0.003, 2-tailed Student’s t test). (I) Kaplan-Meier analysis adjusted for age, sex, FVC, DLCO, and GAP index comparing patients prescribed an α1 adrenergic receptor antagonist (black line, n = 22) to those not on such therapy (red line, n = 67) showed a hazard ratio for all-cause mortality of 0.30 (P = 0.008). *P < 0.05, **P < 0.01, and ***P < 0.001. Data are shown as either median with 95% confidence interval or mean ± SEM.